Although the presence of amyloid in the plaques of Alzheimer's Disease patients was noted over 60 years ago (Divry, 1927), molecular mechanisms that produce amyloid in the aged human brain and for the increased deposition of this fibrous material in Alzheimer's Disease remain unknown. Also undescribed is the contribution, if any, of amyloid to the active process of plaque formation vis-a-vis a secondary and more passive role that indicates only the terminal stages of parenchymal deterioration.
Recently, some progress has been made in defining the partial structure of amyloid fibrillary protein. Glenner et al. (1984a) purified amyloid from meningeal vessels of an AD brain; a 4.2 kD polypeptide was isolated and shown to have a unique 24 amino acid sequence (.beta.-polypeptide, FIG. 1). A polypeptide of similar sequence was subsequently isolated from the cerebrovascular amyloid of a Down's syndrome brain (Glenner et al., 1984b); a single amino acid substitution, of glutamic acid for glutamine at position 11, distinguished the two polypeptides. Similar results were independently obtained by Masters et al. (1985a) who partly purified and analyzed amyloid plaque cores from the AD cerebral cortex; the 28 amino acid sequence of the Glu variant was obtained (A4 sequence, FIG. 1). The A4 sequence differs from the .beta.-polypeptide disclosed by Glenner et al. (U.S. Pat. No. 4,666,829) by the three amino acids at positions 11, 27 and 28. The significance of this report is that the A4 was derived from amyloid plaque cores, a hallmark feature of AD. The amino acid sequence of A4 varies from that of the .beta.-polypeptide derived from vascular amyloid (see FIG. 1).
Using polyclonal antisera to a synthetic .beta.-amyloid polypeptide containing residues 1 through 10 (FIG. 1), it was shown that neuritic plaque amyloid shares antigenic determinants with the similar fibrillary lesion of cerebral vessels (Wong et al.. 1985). The same antisera failed to detect neurofibrillary tangles (NFTs). By contrast, antiserum raised against residues 1 to 11 of the A4 polypeptide failed to detect vascular amyloid or neuritic plaques but, rather, exhibited exclusive specificity for the NFT; and antisera to the A4 peptide extending from residues 11 to 23 stained both plaques and vessels (Masters et al., 1985b). Thus, there is precedent to believe that antibodies to the .eta.-peptide and the A4 peptide are not identical with regard to their specificities.
Glenner et al., U.S. Pat. No. 4,666,829 disclose the preparation of antibodies using the first 10 amino acids of the .beta.-amyloid polypeptide (FIG. 1).